The term "alcoholic hepatitis" denotes a disease characterized histologically by fatty metamorphosis of hepatocytes, polymorphonuclear leukocytic infiltrates, fibrosis and cellular necrosis, and clinically by a moderate-to-severe impairment of liver function and substantial mortality. It is clearly a manifestation of ethanol toxicity and is common. Nonetheless, its pathogenesis is obscure. Despite a voluminous literature on the metabolic effects of ethanol in the liver, there are few clues as to the initiation of the inflammatory lesion of alcoholic hepatitis. In this application, investigators of the Liver Center Laboratory and the Rosalind Russell Arthritis Laboratory at San Francisco General Hospital propose a collaborative approach to this problem. Preliminary studies by these Laboratories have revealed that normal rat hepatocytes in primary culture elaborate a potent chemoattractant for polymorphonuclear leukocytes when incubated with modest concentrations of ethanol. Because this response occurs at relatively low levels of ethanol (5 - 10 mM) and is rapid (detectable within two hours after addition of ethanol to the culture medium), it suggests that leukocytic infiltrates play a primary role in the injury response of the liver. By elaborating oxygen-derived free radicals, leukocytes may stimulate fibrogenesis and cause cellular necrosis. The work outlined to test this hypothesis involves parallel studies of the nature and production of the chemotactic factor and the role of leukocytes in mediating fibrogenesis and cell damage. The findings are expected to provide new insight into the precise sequence of pathologic events in alcoholic hepatitis. They will be relevant as well to a wide array of hepatic diseases, of varying etiology, in which abnormally increased fibrosis is a major lesion.